The development of reliable and convenient methods for solid phase synthesis of polynucleotides has led to many advances in molecular biology and related fields, e.g. Itakura, Science, Vol. 209, pgs. 1401-1405 (1980); Caruthers, Science, Vol. 230, pgs 281-285 (1985); and Eckstein, ed., Oligonucleotdes and Analogues: A Practical Approach (IRL Press, Oxford, 1991). In particular, the availability of synthetic oligonucleotides and a variety of nuclease-resistant analogs, e.g. phosphorothioates, methylphosphonates, and the like, has encouraged investigation into their use as therapeutic compounds for treating a variety of conditions associated with the inappropriate expression of indigenous and/or exogenous genes, e.g. Cohen, Ed., Oligonucleotdes: Antisense Inhibitors of Gene Expression (Macmillan Press, New York, 1989); Van der Krol et al, Biotechniques, Vol. 6, 958-976 (1988); Matsukura et al, Proc. Natl. Acad. Sci., Vol. 86, pgs. 4244-4248 (1989); lyer et al, Nucleic Acids Research, Vol. 18, pgs. 2855-2859 (1990); Leiter et al, Proc. Natl. Acad. Sci., Vol. 87, pgs. 3430-3434 (1990); McManaway et al, Lancet, Vol. 335, pgs. 808-811 (1990); Manson et al, Lymphokine Research, Vol. 9, pgs. 35-42 (1990); Sankar et al, Eur. J. Biochem., Vol. 184, pgs. 39-45 (1989); Agrawal et al, Proc. Natl. Acad. Sci., Vol. 86, pgs. 7790-7794 (1989); Miller, Biotechnology, Vol. 9, pgs. 358-362 (1991); Chiang et al, J. Biol. Chem., Vol. 266, pgs. 18162-18171 (1991); Calabretta, Cancer Research, Vol. 51, pgs. 4505-4510 (1991), and the like. Usually, these compounds are employed as "antisense" compounds. That is, the compounds are oligonucleotides, or analogs thereof, that have a base sequences complementary to segments of target nucleic acids, usually RNAs, such that duplexes or triplexes form that either render the respective targets more susceptible to enzymatic degradation, block translation or processing, or otherwise block or inhibit expression, e.g. Cohen (cited above); Moser et al, Science, Vol. 238, pgs. 645-650 (1987).
Many of the phosphate-analog linkages of these antisense compounds, as well as those of related non-nucleosidic polymers, are chiral at the phosphorus, e.g. phosphorothioates, phosphoroselenoates, methylphosphonates, and the like, Zon, Pharmaceutical Research, Vol. 5, pgs. 539-549 (1988); and Uhlmann and Peyman, Chemical Reviews, Vol. 90, pgs. 543-584 (1990). Currently, there is no way to control the chirality of these phosphorus linkages during solid phase synthesis. Consequently, the synthesis of such polymers results in mixtures of diastereoisomers, wherein the individual polymers of the mixtures have random sequences of R.sub.p and S.sub.p chiral phosphorus linkages along their backbones. Such mixtures prepared by currently available technology consist of 2" diastereoisomers, where n is the number of P-chiral linkages in the polymer. For example, a trimer with two P-chiral linkages has 2.sup.2 =4 possible diastereoisomers, indicated by the following 5'.fwdarw.3' sequences of linkages: R.sub.p -R.sub.p, R.sub.p -S.sub.p, S.sub.p -R.sub.p, and S.sub.p -S.sub.p. In addition to the lack of methods for synthesizing polymers of predetermined chirality, there is also a lack of available analytical tools for direct measurement of the reproducibility of preparing a diastereoisomer population of polymers having P-chiral linkages for anything greater than 4-mers, Zon, pgs. 301-349 in Hancock, Ed., High-Performance Liquid Chromatography in Biotechnology (John Wiley, New York, 1990). The inability to prepare oligonucleotide analogs and related non-nucleosidic polymers with predetermined sequence, length, and chirality is problematic because there is strong evidence that chirality is an important factor in duplex stability and nuclease resistance, e.g. Lesnikowski et al, Nucleic Acids Research, Vol. 18, pgs. 2109-2115 (1990); Burgers et al, J. Biol. Chem., Vol. 254, pgs. 7476-7478 (1979); Miller et al, Biochem., Vol. 18, pgs. 5134-5143 (1979); Zon, Pharmaceutical Research (cited above); Eckstein, Ann. Rev. Biochem., Vol. 54, pgs. 367-402 (1985); and the like. This evidence suggests that stereo-controlled synthesis of antisense and related compounds with predetermined chirality at each P-stereogenic center might allow one to design particular therapeutic diastereoisomers which form maximally stable duplexes and which are maximally resistant towards nucleolytic enzymes, thus increasing their effective life times, and in this way decreasing the required amount of xenobiotic material for a given therapeutic effect.